Sex-dependent microglial colonization and vulnerability to a neonatal infection

项目摘要。 小胶质细胞是大脑的常驻免疫细胞。它们参与了大脑的许多过程 发育，维持神经内稳态，以及对感染或损伤的反应，以及 修理。我们最近发现，发育中的大鼠大脑中小胶质细胞的数量存在显著的性别差异。 出生后第4天，新生雄性大鼠海马区小胶质细胞数量显著多于雌性大鼠， 大脑皮层和杏仁核--大脑中对情绪和认知至关重要的区域。出生时，P0，男性有显著的 两种趋化因子(趋化细胞因子)CCL20和CCL4水平在海马区和 大脑皮层多于雌性。鉴于这些数据，本提案的目的是测试两个相互关联的 假设：(1)新生儿睾酮通过以下途径增加小胶质细胞在发育中的男性大脑中的定植 CCL20和CCL4的表达升高；(2)发育过程中小胶质细胞数量增加 与男性相比，男性大脑增加了男性对新生儿感染影响的易感性 女性。这些数据与流行病学数据相一致，这些数据表明男性更有可能患上 被诊断出患有某些神经发育障碍，也有已知或怀疑的免疫病因， 包括自闭症、多动症、精神分裂症和脑瘫。因此，拟议的实验将探索一种 通过确定小胶质细胞之间的相互作用，从新的角度研究重要的心理健康问题 男性和女性发育中的大脑的定殖化，以及男性对 发育性/认知性大脑障碍。

Project Summary. Microglia are the resident immune cells of the brain. They are involved in many processes of brain development, the maintenance of the neural homeostasis, as well as the response to infection or injury, and repair. We have recently found a striking sex difference in the number of microglia in the developing rat brain. On postnatal day (P) 4 neonatal male rats have significantly more microglia than females in the hippocampus, cortex, and amygdala -- brain regions critical for emotion and cognition. At birth, P0, males have significantly elevated levels of two chemokines (chemotactic cytokines), CCL20 and CCL4, within the hippocampus and cortex than females. Given these data, the purpose of the present proposal is to test two interrelated hypotheses: (1) Neonatal testosterone increases the colonization of microglia in the developing male brain via the elevated expression of CCL20 and CCL4, and (2) Increased numbers of microglia within the developing male brain increases the vulnerability of males to the effects of a neonatal infection when compared to females. These data are consistent with epidemiological data that indicate males are more likely to be diagnosed with certain neurodevelopmental disorders that also have known or suspected immune etiologies, including autism, ADHD, schizophrenia, and cerebral palsy. Thus the proposed experiments will explore an important mental health issue from a novel perspective by identifying the interaction between microglial colonization of the developing brain in males and females, and the sex-dependent vulnerability of males to developmental/cognitive brain disorders.